Fatigue fracture occurs when a structure is loaded many times with a force which would not cause fracture if applied only once. Each cycle produces minute damage which accumulates until fracture occurs. In bone, fatigue damage is repaired by remodeling. When remodeling does not keep pace, fatigue or "stress" fractures may result; these are common among race-horses, military trainees, ballet dancers, and recreational as well as competitive runners. However, it is also hypothesized that fatigue damage increases bone fragility in many other individuals, including those with osteoporosis and other metabolic bone diseases. Thus, the clinical significance of fatigue may be very great. Experimental studies of fatigue in bone have been of two kinds. Some have fatigue tested specimens to failure, studying the number of cycles required to fracture a specimen under a given load. Other investigators have studied the existence of histologically observable microcracks in bone with the view that such cracks are fatigue damage. While it has been shown that the number of microcracks increases following repetitive loading, the relationships between histologic microcracks, bone fragility, and fatigue failure are presently unknown. Clearly, the hypothesis that microcracks cause fragility or fatigue fracture if they are not repaired needs to be directly tested. The relationships between microcracks, fatigue damage, fragility, and fatigue failure need to be worked out phenomenologically and mechanistically. The proposed research will address this problem via two in vitro experiments employing fatigue loading in 4 point bending of the equine metacarpal bone. Experiment 1 will test for an association between microcracks and diminishment of the elastic modulus (another measure of fatigue damage). It will also test whether these two forms of damage accumulate as predictable functions of stress magnitude and the number of load cycles applied, to the point of fatigue fracture. Experiment 2 will determine whether microcracks and stiffness damage affect bone's resistance to traumatic fracture. In addition, theoretical modeling will explore the mechanisms by which histologic damage alters strength and stiffness.